Histidine 141 is critical for GABArho1 receptor sensitivity to ascorbic acid.

CI CALERO, DJ CALVO

Huerta Grande Cordoba

Congreso; II RCN, Segunda Reunión Conjunta de Neurociencias. Sociedad Argentina de Neurociencias y Taller Argentino de Neurociencias; 2010

Sociedad Argentina de Neurociencias y Taller Argentino de Neurociencias

Neurotransmitter receptors, including ionotropic GABA receptors, can be regulated by redox mechanisms. We showed that homomeric rho1 GABAC receptors (GABAr1-R) are modulated by ascorbic acid (Asc) and other redox agents (Calero and Calvo, 2008). Asc modulation was partially explained by a chemical modification of the SH-groups at two extracellular cysteines forming the cys-loop (C177 and C191) of GABAr1-R. However, we also showed an additional allosteric mechanism involved. Histidine 141 (H141) is essential for allosteric effects induced by Zn2+ on GABAr1-R. In order to determine if this aminoacidic residue also participates in the mechanism of Asc modulation, we used site-directed mutagenesis. Wild type and mutant receptors were expressed in X. laevis oocytes and GABA-evoked Cl- currents electrophysiologically recorded. Maximal responses mediated by H141D GABAr1-R were significantly potentiated by 3 mM Asc, as observed for wt GABAr1-R. However, Asc was unable to produce shifts in the EC50 of D-R curves of receptors carrying the mutation. Our results suggest that H141 is involved in the allosteric effects evoked by Asc on GABAr1-R.